The gut hormone ghrelin is released by gastric endocrine cells and acts as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Increased circulating levels of ghrelin are associated with increased hunger, food intake, and gastric emptying. This latter function is of interest due to the clinical importance of postoperative gastric ileus and the lack of effective prokinetic therapies. The mechanisms by which ghrelin accelerates gastric emptying have been investigated using a number of physiological approaches, and an important role for the vagus nerve has been identified, but no published study to date has directly investigated vagal efferent nor single unit afferent activity evoked by ghrelin, and thus, details of vagal signaling in response to ghrelin remain obscure. Moreover, preliminary data obtained by our laboratory and others contradict the initial published hypothesis that the mechanism of ghrelin's prokinetic action depends on vagal afferent input. The proposed work will investigate the detailed visceral neuronal signaling evoked by systemic ghrelin administration, using a combination of two novel techniques we have recently developed: gastric ultrasonomicrometry to monitor motility, and a unique dual recording technique allowing simultaneous monitoring of single unit vagal efferent and afferent activity. The experiments will test the hypotheses that 1) systemic ghrelin acts centrally to increase vagal efferent activity, 2) that neither vagal nor splanchnic afferent input is required to mediate this vagal efferent excitation, 3) that systemic ghrelin acts at GHS-R in the caudal brainstem to increase vagal efferent outflow, and 4) that increased gastric motility evoked by ghrelin occurs via a combination of vagally-mediated and vagal-independent mechanisms. The work will characterize the particular subclasses of vagal afferent and efferent fiber types whose activity is modified by systemic ghrelin. The combination of techniques will allow discrimination of temporal relationships between afferent and efferent discharge and motility in discrete gastric regions, including sphincters, and will distinguish the components of gastric regional and sphincter motility mediated via vagal- dependent and -independent pathways. This work will directly address the neural mechanisms mediating ghrelin's effects on motility, and provide a foundation for a new approach to understanding the integrated role of vagal and endocrine signaling in the modulation of gut function by a wide range of gut hormones. [unreadable] [unreadable] [unreadable]